The worldwide epidemics of HIV/AIDS and substance abuse adversely affect tens of millions of people. Injection drug use (IDU), largely of opiates, is the second most frequent route of acquisition of HIV in the US and most frequent in many Western European countries. The world's most volatile emerging HIV epidemics are fueled by illicit drug use in the former Soviet Union, other Eastern European countries,[1] Southeast Asia, China and other Western Pacific countries. HIV/AIDS and related co morbid conditions, including hepatitis C (HCV) and tuberculosis (TB), are the major causes of morbidity and mortality among drug users. HCV, highly prevalent among drug users in the US, particularly in those co-infected with HIV, is a major cause of liver failure and death. One third of the world's population is infected with micro bacterium TB, with increasing numbers in IDUs with HIV co infection. Substantial advances in the treatment of chemical dependency and dramatic advances in HIV/AIDS treatment have been made in past decades. The success of antiretroviral therapy and treatment for other co morbid conditions such as TB and HCV in substance abusers requires concomitant treatment of substance abuse. Problematic drug interactions between therapies for HIV, and substance abuse and TB and HCV therapies as well can blunt or reverse therapeutic .benefits for each and all of these diseases. Our group performed the first studies of drug interactions with antiretroviral and substances abuse therapies and have continued to work productively in this area over the past two decades. We now propose pharmacokinetic and pharmacodynamic study of drug interactions with exciting new antiretroviral therapies. These studies will form the first specific aim of this proposal. As second and third aims, we will broaden our work with substance abuse and new antiretroviral therapies to address critical drug interactions between TB and HCV and .substance abuse therapies. To accomplish these aims, we propose three critical studies of antiretroviral and substance abuse therapy, two important neglected studies of TB and substance abuse therapies, one study of TB, substance abuse and antiretroviral and one study of the most promising HCV therapy, in a logical sequential order over the five year course of this grant. This work will be performed by a highly experienced and interactive team, expert in the treatment of substance abuse, HIV/AIDS and TB and HCV, the conditions targeted by this proposal. This team is skilled and productive in the performance of phase I, II, III and IV clinical trials with injection drug users and other vulnerable populations. Public Health Relevance: Injection drug users have high rates of HIV/AIDS and other infectious diseases which are responsible for illness and death. Treatment of substance abuse is necessary for successful treatment of these infections, but interactions between different drugs interfere with treatment success. This grant will perform studies to identify these interactions and improve the treatment of these conditions in this vulnerable population.